"Of Mice and Microbes"

by Justine Wang

A significant number of childhood deaths worldwide are linked to one particular menace: malnutrition. Last year, 5.9 million children did not live past the age of five. In almost half of these cases, malnutrition was the underlying contributor to their deaths. For us, living in one of the foremost developed nations in the world, a severe lack of substantial nutrition is nearly impossible to imagine. After all, the afflictions that plague America today, such as obesity and diabetes, arise from a culture of excess. Many of us have only a superficial understanding of malnutrition and what can be done to combat it.

At first glance, the solution to a lack of proper nutrition would be to simply provide the necessary food, correct? Yes—but perhaps not completely so. To find the ultimate solution for malnutrition, we may need to look somewhere outside of food entirely—that is, something independent of how much we eat or even what we eat: the germs inside of us.

Inspiration

Microbes such as bacteria and archaea live in and on all parts of our bodies, outnumbering our own human cells by a ten to one ratio. The community of all our microbial companions is called our microbiota. Pediatrician Mark Manary of Washington University in St. Louis became interested in the potential role of microbiota living in our gut and a severe acute form of malnutrition called kwashiorkor. Dr. Manary was inspired by his work with children in Malawi, a country in which pediatric malnutrition is constant and widespread. In a study published in 2013, he observed 317 pairs of Malawian twins from birth through age three, and noticed that in half of the pairs he studied, only one of the two twins developed malnutrition, despite similarity in diet, lifestyle and genetics.

Manary then studied 13 pairs of these twins discordant for kwashiorkor while treating them with ready-to-use therapeutic food (RUTF), one of his own developments made from peanut paste, sugar, vegetable oil and fortified milk. At the same time, his team was collecting data on the children’s gut microbiota and isolating their microbial DNA from fecal samples. Taking it a step further, Manary transplanted the microbes from the fecal samples into mice to observe how the microbial population could affect kwashiorkor development within a smaller microcosm.

The results were telling.

Experiment

During the first three weeks of the study, the mice were fed according to a typical Malawian diet. The mice that received microbes from the kwashiorkor twins lost significantly more weight and became severely anorexic, dropping to as low as about 65 percent of their original weight. On the other hand, the mice that received microbes from the healthy children lost a much smaller amount of weight and were able to maintain more than 90 percent of their original weight. The mice were then fed RUTF for two weeks, and both the kwashiorkor and healthy mice quickly gained weight. However, the kwashiorkor mice were not able to return to their original weight, while the healthy mice managed to exceed their starting weight. To explain the differences in response, Manary turned to analysis at the cellular level by looking at how the microbial populations in the mice were changing.

Results

The kwashiorkor microbiota revealed several startling observations. As humans age, grow and develop, the composition of our gut microbiota changes as well. However, the microbiota of the undernourished children appeared similar to the microbiota one would expect to see in much younger children, suggesting that the microbial population itself was also stunted and immature. The kwashiorkor mice had a comparatively high proportion of certain species of bacteria, including one that is associated with inflammatory bowel disease. Urine from the kwashiorkor mice revealed evidence of inhibition of an enzyme involved in the Krebs cycle, an important process of cellular respiration and energy metabolism. Enzymes are proteins that facilitate many of the reactions that happen in our bodies, allowing them to occur at a sufficient rate to sustain life. When enzymes of the Krebs cycle are impaired, the result is diminished capacity to metabolize and gain energy from the nutrients we consume.

Based on the data, Manary believes that the microbes from the kwashiorkor children produce substances that prevent our Krebs cycle enzymes from functioning properly, contributing to the children’s malnourished condition. By the end of the study, Manary and his team had gathered enough evidence to conclude that the makeup of our gut microbiota is a major causal factor in the development of the stunted growth and inhibited weight gain characteristic of kwashiorkor.

Support

Similarly, Jeff Gordon from Washington University in St. Louis conducted another study and strengthened the relationship between malnutrition and microbes. Building off Manary’s work, he supplemented the diet of the malnourished mice with two strains of microbes, Ruminococcus gnavus and Clostridium symbiosum. The addition of these bacteria overcame the effects of undernutrition in the mice, allowing them to grow despite their poor diet.

Another strain of bacteria, Lactobacillus plantarum, was recently shown by biologist François Leulier to boost growth in young mice by stimulating production of a growth hormone factor, even though the mice were also undernourished. The authors of all of these studies were able to demonstrate and conclude a causal relationship between the maturity of gut microbiota, the types of microbial species present and response to undernutrition.

Moving Forward

For the healthcare professionals and scientists looking to eradicate this form of global suffering, malnutrition has been a subject of much study and attention. Fortunately, knowledge from their studies is offering new perspectives on treating this affliction. What we are now certain of is that an improved diet alone is insufficient to treat this preventable condition. A mature, complete community of microbes in our gut must complement improved nutrition, in order to maximize child growth and development, and to treat malnutrition holistically. This two-pronged approach may be the key to closing the gap in the combat against malnutrition, suggesting treatments, such as probiotics with specific strains of bacteria, to promote growth and resist the effects of nutrient deficiency.

As does any treatment working to manipulate the balance of microscopic life, the development of these probiotic treatments comes with its own caution and considerations. Nevertheless, the hope offered by these studies is worth pursuing to decrease global suffering in the lives of millions of young children.